Geneticists say they've built a
working yeast chromosome from the bottom up for the first time — a feat
that could open the way for custom-made biofactories that churn out
fuels and pharmaceuticals.
"We
think this is going to be critical as we transition as a species from a
petroleum economy to a bio-economy," said Jef Boeke, a researcher at NYU
Langone Medical Center who pioneered the project.
Boeke and his colleagues laid out the procedure in a paper published online Thursday by the journal Science.
The work follows up on past achievements in synthetic biology, including the creation of the first synthetic bacterial cells in 2010. The international project in which Boeke is involved, known as Sc2.0,
is different in that it's reconstructing an organism's genetic code
piece by piece, gradually remaking the machinery to control a cell
rather than plugging in an entire genome at once.
The
fact that the cell happens to be brewer's yeast, known scientifically
as Saccharomyces cerevisiae, opens many more doors to potential
applications. Genetically tweaked versions of yeast are already being
used to make biofuel as well as ingredients for an anti-malaria drug.
Boeke
said the technique that was used to create a chromosome could provide
more opportunities for that kind of bio-manufacturing. He's even looking
into creating entirely new yeast chromosomes that incorporate human
genetic code for medical screening purposes.
"This
is significant as an example of synthetic genomes aimed well beyond
making mere copies of chromosomes," Harvard geneticist George Church,
who was not involved in the project, told NBC News. He said the study
reflected a new trend toward "making significant functional changes —
ideally, changes useful for biotech productivity and safety."
How it was done
Chromosomes
are strings of genes that contain the instructions for all the
functions within a cell. Human cells typically contain 23 pairs of
chromosomes. Yeast cells have 16 pairs. The Science paper describes the
reconstruction of yeast chromosome III, which regulates mating behavior and other functions.
The project took seven
years to complete, starting with the assembly of tiny bits of genetic
code by more than 100 students who participated in a program called "Build-a-Genome."
Boeke
compared the job to writing a crowdsourced book, where every letter of
the book is a DNA base pair. At the lowest level, 50 to 75 base-pair
letters were combined into words. Those words were strung together into
paragraphs consisting of 750 to 1,000 base pairs. The paragraphs were
combined into 3,000-word pages, and then the pages were assembled into
11 separate chapters of genetic code.
Each
chapter was edited to change or delete code. The researchers omitted
what appeared to be needless words — what's popularly known as "junk
DNA." They also inserted strings of DNA to serve as identifying markers,
as well as codes for shuffling the genes in the chromosome like
sections in a loose-leaf binder.
Lucy Reading-Ikkanda
The researchers started out
with 316,617 base pairs in the natural chromosome, and slimmed the code
down to 272,871 base pairs. More than 500 genetic alterations were made
along the way.
"We didn't know
ahead of time whether it was going to work out or not," Boeke said. "We
know of many instances where we make one single base change and it will
kill the yeast dead."
Boeke and his colleagues
swapped their synthetic code into live yeast cells, chapter by chapter,
to check their work. They were relieved to find that the yeast cells
with the synthetic chromosome, called SynIII, generally functioned as
well as cells with the natural chromosome.
Then the researchers used a technology called SCRaMbLE
(Synthetic Chromosome Recombination and Modification by LoxP-mediated
Evolution) to shuffle the genes in the synthetic chromosome. They
"scrambled" the genes to turn a sterile yeast cell into a yeast cell
that could mate.
"It shows that,
using the scrambling system, we can really transfer a new property to
the yeast," Boeke told NBC News. "I think we're going to be able to show
many more examples of this in the future."
Perils and possibilities
Boeke
said SynIII marked only the beginning of a total yeast makeover. "We
still have 15 chromosomes to go," he noted. The entire task could take
at least a couple of years to complete.
In
an email exchange with NBC News, Church noted that the techniques
described in the Science paper were complementary to other strategies
for accelerated evolution, such as MAGE and CRISPR. "The impacts (good and bad) typically do not become significant until these strategies are applied genome-wide," Church said.
Boeke
noted that the yeast strains used for the Sc2.0 project have been
specifically designed for laboratory use, and have to be fed nutrients
to survive. "In nature, such strains don't do well in the world at all,"
he said. That's just one of the safeguards aimed at keeping undesirable
mutant yeast strains from getting into the wild.
"We're very careful to build safety into the projects," Boeke said.
In
the future, the yeast genome could be tweaked to make the cells more
tolerant to alcohol — opening the way to more efficient biofuel
production. Boeke said he's also studying ways to create
neo-chromosomes, or "add-on" chromosomes, that incorporate custom-made
genetic code for a wide variety of applications.
"One
that we're pretty excited about is a network of human genes that we can
bring into the yeast," Boeke said. "These genes are involved in a
series of unsolved metabolic diseases that there's no treatment for. We
think that by bringing this neo-chromosome into the yeast, we might be
able to develop some good models to understand those diseases better,
and perhaps even to develop some therapeutic agents. I do work at a
medical school, so I'm always paying attention to these applications."
